AMPA Component Research Articles

A prefrontal network model operating near steady and oscillatory states links spike desynchronization and synaptic deficits in schizophrenia.

Schizophrenia results in part from a failure of prefrontal networks but we lack full understanding of how disruptions at a synaptic level cause failures at the network level. This is a crucial gap in our understanding because it prevents us from discovering how genetic mutations and environmental risks that alter synaptic function cause prefrontal network to fail in schizophrenia. To address that question, we developed a recurrent spiking network model of prefrontal local circuits that can explain the link between NMDAR synaptic and 0-lag spike synchrony deficits we recently observed in a pharmacological monkey model of prefrontal network failure in schizophrenia. We analyze how the balance between AMPA and NMDA components of recurrent excitation and GABA inhibition in the network influence oscillatory spike synchrony to inform the biological data. We show that reducing recurrent NMDAR synaptic currents prevents the network from shifting from a steady to oscillatory state in response to extrinsic inputs such as might occur during behavior. These findings strongly parallel dynamic modulation of 0-lag spike synchrony we observed between neurons in monkey prefrontal cortex during behavior, as well as the suppression of this 0-lag spiking by administration of NMDAR antagonists. As such, our cortical network model provides a plausible mechanism explaining the link between NMDAR synaptic and 0-lag spike synchrony deficits observed in a pharmacological monkey model of prefrontal network failure in schizophrenia.

Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease

Patients affected by chronic kidney disease (CKD) have an increased risk of developing cognitive impairment. The cause of mental health disorders in CKD and in chronic hemodialysis patients is multifactorial, due to the interaction of classical cardiovascular disease risk factors, kidney- and dialysis-related risk factors with depression, and multiple drugs overuse. A large number of compounds, defined as uremic toxins that normally are excreted by healthy kidneys, accumulate in the circulations, in the tissues, and in the organs of CKD patients. Among the candidate uremic toxins are several guanidino compounds, such as Guanidine. Uremic toxins may also accumulate in the brain and may have detrimental effects on cerebral resident cells (neurons, astrocytes, microglia) and microcirculation. The present study aims to analyze the effect of Guanidine on hippocampal excitatory postsynaptic field potentials (fEPSPs) and in CA1 pyramidal neurons recorded intracellularly. Moreover, we compared these effects with the alterations induced in vitro by CKD patients derived serum samples. Our results show an increased, dose-dependent, synaptic activity in the CA1 area in response to both synthetic Guanidine and patient’s serum, through a mechanism involving glutamatergic transmission. In particular, the concomitant increase of both NMDA and AMPA component of the excitatory postsynaptic currents (EPSCs) suggests a presynaptic mechanism. Interestingly, in presence of the lower dose of guanidine, we measure a significant reduction of EPSCs, in fact the compound does not inhibit GABA receptors allowing their inhibitory effect of glutamate release. These findings suggest that cognitive symptoms induced by the increase of uremic compounds in the serum of CKD patients are caused, at least in part, by an increased glutamatergic transmission in the hippocampus.

New insights into methoxetamine mechanisms of action: Focus on serotonergic 5-HT2 receptors in pharmacological and behavioral effects in the rat

Methoxetamine (MXE) is a dissociative substance of the arylcyclohexylamine class that has been present on the designer drug market as a ketamine-substitute since 2010. We have previously shown that MXE (i) possesses ketamine-like discriminative and positive rewarding effects in rats, (ii) affects brain processing involved in cognition and emotional responses, (iii) causes long-lasting behavioral abnormalities and neurotoxicity in rats and (iv) induces neurological, sensorimotor and cardiorespiratory alterations in mice. To shed light on the mechanisms through which MXE exerts its effects, we conducted a multidisciplinary study to evaluate the various neurotransmitter systems presumably involved in its actions on the brain. In vivo microdialysis study first showed that a single administration of MXE (0.25 and 0.5 mg/kg, i.v.) is able to significantly alter serotonin levels in the rat medial prefrontal cortex (mPFC) and nucleus accumbens. Then, we observed that blockade of the serotonin 5-HT2 receptors through two selective antagonists, ketanserin (0.1 mg/kg, i.p.) and MDL 100907 (0.03 mg/kg, i.p.), at doses not affecting animals behavior per se, attenuated the facilitatory motor effect and the inhibition on visual sensory responses induced by MXE (3 mg/kg, i.p.) and ketamine (3 mg/kg, i.p.), and prevented MXE-induced reduction of the prepulse inhibition in rats, pointing to the 5-HT2 receptors as a key target for the recently described MXE-induced sensorimotor effects. Finally, in-vitro electrophysiological studies revealed that the GABAergic and glutamatergic systems are also likely involved in the mechanisms through which MXE exerts its central effects since MXE inhibits, in a concentration-dependent manner, NMDA-mediated field postsynaptic potentials and GABA-mediated spontaneous currents. Conversely, MXE failed to alter both the AMPA component of field potentials and presynaptic glutamate release, and seems not to interfere with the endocannabinoid-mediated effects on mPFC GABAergic synapses. Altogether, our results support the notion of MXE as a NMDA receptor antagonist and shed further lights into the central mechanisms of action of this ketamine-substitute by pointing to serotonin 5-HT2 receptors as crucial players in the expression of its sensorimotor altering effects and to the NMDA and GABA receptors as potential further important targets of action.

Multiple synaptic connections into a single cortical pyramidal cell or interneuron in the anterior cingulate cortex of adult mice

The ACC is an important brain area for the processing of pain-related information. Studies of synaptic connections within the ACC provide an understanding of basic cellular and molecular mechanisms for brain functions such as pain, emotion and related cognitive functions. Previous study of ACC synaptic transmission mainly focused on presumably thalamic inputs into pyramidal cells. In the present study, we developed a new mapping technique by combining single neuron whole-cell patch-clamp recording with 64 multi-channel field potential recording (MED64) to examine the properties of excitatory inputs into a single neuron in the ACC. We found that a single patched pyramidal neuron or interneuron simultaneously received heterogeneous excitatory synaptic innervations from different subregions (ventral, dorsal, deep, and superficial layers) in the ACC. Conduction velocity is faster as stimulation distance increases in pyramidal neurons. Fast-spiking interneurons (FS-IN) show slower inactivation when compared to pyramidal neurons and regular-spiking interneurons (RS-IN) while pyramidal neurons displayed the most rapid activation. Bath application of non-competitive AMPA receptor antagonist GYKI 53655 followed by CNQX revealed that both FS-INs and RS-INs have AMPA and KA mediated components. Our studies provide a new strategy and technique for studying the network of synaptic connections.

Chronic in vivo optogenetic stimulation modulates neuronal excitability, spine morphology, and Hebbian plasticity in the mouse hippocampus.

Prolonged increases in excitation can trigger cell-wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes, and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, (b) modulate synaptic currents that might compensate for chronic excitation, and (c) lead to alterations in Hebbian plasticity. After 24 hr of stimulation with 15-ms blue light pulses every 90 s, dendritic spine density and area were reduced in the CA1 region of mice expressing channelrhodopsin-2 (ChR2) when compared to controls. This protocol also reduced the amplitude of mEPSCs for both the AMPA and NMDA components in ex vivo slices obtained from ChR2-expressing mice immediately after the end of stimulation. Finally, chronic stimulation impaired the induction of LTP and facilitated that of LTD in these slices. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.

Microglia shape presynaptic properties at developing glutamatergic synapses.

Deficient neuron-microglia signaling during brain development is associated with abnormal synaptic maturation. However, the precise impact of deficient microglia function on synaptic maturation and the mechanisms involved remain poorly defined. Here we report that mice defective in neuron-to-microglia signaling via the fractalkine receptor (Cx3cr1 KO) show reduced microglial branching and altered motility and develop widespread deficits in glutamatergic neurotransmission. We characterized the functional properties of CA3-CA1 synapses in hippocampal slices from these mice and found that they display altered glutamatergic release probability, maintaining immature properties also at late developmental stages. In particular, CA1 synapses of Cx3cr1 KO show (i) immature AMPA/NMDA ratio across developmental time, displaying a normal NMDA component and a defective AMPA component of EPSC; (ii) defective functional connectivity, as demonstrated by reduced current amplitudes in the input/output curve; and (iii) greater facilitation in the paired pulse ratio (PPR), suggesting decreased release probability. In addition, minimal stimulation experiments revealed that excitatory synapses have normal potency, but an increased number of failures, confirming a deficit in presynaptic release. Consistently, KO mice were characterized by higher number of silent synapses in comparison to WT. The presynaptic deficits were corrected by performing experiments in conditions of high release probability (Ca2+ /Mg2+ ratio 8), where excitatory synapses showed normal synaptic multiplicity, AMPA/NMDA ratio, and proportion of silent synapses. These results establish that neuron-microglia interactions profoundly influence the functional maturation of excitatory presynaptic function.

The alterations of neurophysiological parameters of the anterior cingulate cortex in the experimental depressive syndrome of different genesis

The rostral anterior cingulate cortex (ACC) is important unit of the brain default mode network. An operation of this network is overset in depressive disorders of different genesis. A hyperactivity of ACC marks this overset. Neurophysiological nature of ACC hyperactivity do not elucidate. It was reproduced a behavioral depression in experiments on the rats evoke by either chronic inflammation of back skin or depletion of level of the monoamines in the brain administration of reserpine. The level of rat depression behavior estimated on the data of scores of forced swimming test. It was ascertained in electrophysi-ological researches on brain slices comprising ACC that depressogenic procedures evoked appearance of pathological synaptic plasticity (analog of the long-term potentiation) in superficial II/III layers pyramidal neurons. This pathological plasticity appeared by increasing of the amplitudes of field EPSPs and their AMPA and NMDA components; it was due by gain of the presynaptic glutamate releasing and possible rising of the postsynaptic receptors chemosensitivity. Pathological synaptic plasticity occluded tetanus-induced longterm potentiation in these layers of ACC. The neurophysiological changes in deep V layer of ACC were inconsiderable, however it was ascertained inhibition of tetanus-induced long-term potentiation expression.

GSK-3β inhibitors reverse cocaine-induced synaptic transmission dysfunction in the nucleus accumbens.

Nucleus accumbens receives glutamatergic projection from the prefrontal cortex (PFC) and dopaminergic input from the Ventral tegmental area (VTA). Recent studies have suggested a critical role for serine/threonine kinase glycogen synthase kinase 3β (GSK3β) in cocaine-induced hyperactivity; however, the effect of GSK3β on the modulation of glutamatergic and dopaminergic afferents is unclear. In this study, we found that the GSK3 inhibitors, LiCl (100 mg/kg, i.p.) or SB216763 (2.5 mg/kg, i.p.), blocked the cocaine-induced hyperlocomotor activity in rats. By employing single-unit recordings in vivo, we found that pretreatment with either SB216763 or LiCl for 15 min reversed the cocaine-inhibited firing frequency of medium spiny neuron (MSN) in the nucleus accumbens (NAc). Preperfusion of SB216763 (5 μM) ameliorated the inhibitory effect of cocaine on both the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (up to 99 ± 6.8% inhibition) and N-methyl-D-aspartic acid receptor (NMDAR)-mediate EPSC (up to 73 ± 9.7% inhibition) in the NAc in brain slices. The effect of cocaine on AMPA and NMDA receptor-mediate excitatory postsynaptic current (EPSC) were mimicked by the D1 -like receptor agonist SKF 38393 and blocked by the D1 -like receptor antagonist SCH 23390, whereas D2 -like receptor agonist or antagonist failed to mimic or to block the action of cocaine. Preperfusion of SB216763 for 5 min also ameliorated the inhibitory effect of SKF38393 on both AMPA and NMDA receptor-mediated components of EPSC, indicate the effect of SB216763 on cocaine was via the D1 -like receptor. Moreover, cocaine inhibited the presynaptic release of glutamate in the NAc, and SB216763 reversed this effect. In conclusion, D1 receptor-GSK3β pathway, which mediates glutamatergic transmission in the NAc core through a presynaptic mechanism, plays an important role in acute cocaine-induced hyperlocomotion.

Novel NMDA receptor-specific desensitization/inactivation produced by ingestion of the neurotoxins, β-N-methylamino-l-alanine (BMAA) or β-N-oxalylamino-l-alanine (BOAA/β-ODAP)

The environmental neurotoxins BMAA (β-N-methylamino-l-alanine) and BOAA (β-N-oxalylamino-l-alanine) are implicated as possible causative agents for the neurodegenerative diseases, amyotrophic lateral sclerosis/ParkinsonismDementia complex (ALS/PDC) and neurolathyrism, respectively. Both are structural analogs of the neurotransmitter, glutamate, and bind postsynaptic glutamate receptors. In this study, the effect of ingestion of these toxins on the response of a singly-innervated, identified, glutamatergic postsynaptic cell in a living, undissected Drosophila is observed by intracellular recording. Previously we have reported that ingested BMAA behaves as an NMDA agonist that produces an abnormal NMDA response in the postsynaptic cell. It is shown here that BOAA also behaves as an NMDA agonist, and produces an effect very similar to that of BMAA on the postsynaptic response. In response to a single stimulus, the amplitude of the NMDA component is decreased, while the time to peak and duration of the NMDA component are greatly increased. No discernable effect on the AMPA component of the response was observed. Furthermore, both BMAA and BOAA cause an NMDAR-specific desensitization in response to repetitive stimulation at the physiological frequency for the postsynaptic cell (5Hz). The possibility that this phenomenon may represent a response to excessive Ca2+ entry through NMDAR channels is discussed. This desensitization phenomenon, as well as the abnormal NMDAR gating characteristics induced by BMAA, appears to be rescued during higher frequency stimulation (e.g. 10, 20Hz).

What a nostril knows: Olfactory nerve-evoked AMPA responses increase while NMDA responses decrease at 24-h post-training for lateralized odor preference memory in neonate rat

Increased AMPA signaling is proposed to mediate long-term memory. Rat neonates acquire odor preferences in a single olfactory bulb if one nostril is occluded at training. Memory testing here confirmed that only trained bulbs support increased odor preference at 24 h. Olfactory nerve field potentials were tested at 24 h in slices from trained and untrained bulbs. A larger AMPA component and a smaller NMDA component characterized responses in the bulb receiving odor preference training. Field potential changes were not seen in a bulbar region separate from the lateral odor-encoding area. These results support models in which memory is mediated by increased olfactory nerve-mitral cell AMPA signaling, and memory stability is promoted by decreased NMDA-mediated signaling.

A Novel Form of Low-Frequency Hippocampal Mossy Fiber Plasticity Induced by Bimodal mGlu1 Receptor Signaling

Mossy fiber synapses act as the critical mediators of highly dynamic communication between hippocampal granule cells in the dentate gyrus and CA3 pyramidal neurons. Excitatory synaptic strength at mossy fiber to CA3 pyramidal cell synapses is potentiated rapidly and reversibly by brief trains of low-frequency stimulation of mossy fiber axons. We show that slight modifications to the pattern of stimulation convert this short-term potentiation into prolonged synaptic strengthening lasting tens of minutes in rodent hippocampal slices. This low-frequency potentiation of mossy fiber EPSCs requires postsynaptic mGlu1 receptors for induction but is expressed presynaptically as an increased release probability and therefore impacts both AMPA and NMDA components of the mossy fiber EPSC. A nonconventional signaling pathway initiated by mGlu1 receptors contributes to induction of plasticity, because EPSC potentiation was prevented by a tyrosine kinase inhibitor and only partially reduced by guanosine 5'-O-(2-thiodiphosphate). A slowly reversible state of enhanced synaptic efficacy could serve as a mechanism for altering the integrative properties of this synapse within a relatively broad temporal window.

D4 Dopamine Receptors Modulate NR2B NMDA Receptors and LTP in Stratum Oriens of Hippocampal CA1

Dopamine plays an important role in synaptic plasticity and learning and is involved in the pathogenesis of various neurological and psychiatric disorders. Here, we reveal staining of dopaminergic fibers in stratum oriens of the mouse hippocampal CA1 region, a finding that is consistent with earlier reports. Furthermore, we examined the effect of dopamine agonists on NMDAR-dependent early long-term potentiation (LTP) (40 min) during γ-aminobutyric acid (GABA)(A)-mediated blockade. LTP of the AMPA component was strongly reduced in stratum oriens but barely affected in stratum radiatum. This layer-specific effect was caused by D4 receptor activation, which augmented the inactivation of synaptic NMDAR-mediated currents (NMDA EPSCs) during LTP induction through a Ca(2+)-dependent G-protein-independent mechanism. A similar dopaminergic modulation of both NMDA EPSCs and LTP was also observed in mice constitutively lacking NR2A but was absent in mice lacking NR2B in principal forebrain neurons. Together, these experiments strongly indicate that dopaminergic modulation of early LTP in stratum oriens occurs through NMDARs containing NR2B subunits via D4Rs. Thus, a dopamine hyperfunction in stratum oriens may result in NMDAR hypofunction that could affect both normal and pathological conditions.

Functional circuitry of a unique cerebellar specialization: the valvula cerebelli of a mormyrid fish

The valvula cerebelli of the mormyrid electric fish is a useful site for the study of cerebellar function. The valvula forms a part of the electrosensory-electromotor system of this fish, a system that offers many possibilities for the study of sensory-motor integration. The valvula also has a number of histological features not present in mammals which facilitate investigation of cerebellar circuitry and its plasticity. This initial study characterizes the basic physiology and pharmacology of cells in the valvula using an in vitro slice preparation. Intrinsic properties and synaptic responses of Purkinje cells and other cell types were examined. We found that Purkinje cells fire a small narrow Na + spike and a large broad Ca 2+ spike, generated in the axon initial segment and dendritic-soma region, respectively. Purkinje cells respond to parallel fiber inputs with graded excitatory postsynaptic potentials (EPSPs) and to climbing fiber inputs with all-or-none EPSPs. Efferent cells, Golgi cells, and deep stellate cells all fire a single type of large narrow spike and respond only to parallel fiber inputs. Both parallel fiber and climbing fiber responses in Purkinje cells appear to be entirely mediated by AMPA-type glutamate receptors, whereas parallel fiber responses in efferent cells and stellate cells include AMPA and NMDA components. In addition, a strong synaptic inhibition was uncovered in both Purkinje cells and efferent cells in response to the focal stimulation of parallel fibers. Dual cell recordings indicate that deep stellate cells contribute at least partially to this inhibition. We conclude that despite its unique histology, the local functional circuitry of the mormyrid valvula cerebelli is largely similar to that of the mammalian cerebellum. Thus, what is learned concerning the functioning of the mormyrid valvula cerebelli may be expected to be informative about cerebellar function in general.

Auditory nerve fibers excite targets through synapses that vary in convergence, strength, and short-term plasticity.

Auditory nerve fibers are the major source of excitation to the three groups of principal cells of the ventral cochlear nucleus (VCN), bushy, T stellate, and octopus cells. Shock-evoked excitatory postsynaptic currents (eEPSCs) in slices from mice showed systematic differences between groups of principal cells, indicating that target cells contribute to determining pre- and postsynaptic properties of synapses from spiral ganglion cells. Bushy cells likely to be small spherical bushy cells receive no more than three, most often two, excitatory inputs; those likely to be globular bushy cells receive at least four, most likely five, inputs. T stellate cells receive 6.5 inputs. Octopus cells receive >60 inputs. The N-methyl-d-aspartate (NMDA) components of eEPSCs were largest in T stellate, smaller in bushy, and smallest in octopus cells, and they were larger in neurons from younger than older mice. The average AMPA conductance of a unitary input is 22 ± 15 nS in both groups of bushy cells, <1.5 nS in octopus cells, and 4.6 ± 3 nS in T stellate cells. Sensitivity to philanthotoxin (PhTX) and rectification in the intracellular presence of spermine indicate that AMPA receptors that mediate eEPSCs in T stellate cells contain more GluR2 subunits than those in bushy and octopus cells. The AMPA components of eEPSCs were briefer in bushy (0.5 ms half-width) than in T stellate and octopus cells (0.8-0.9 ms half-width). Widening of eEPSCs in the presence of cyclothiazide (CTZ) indicates that desensitization shortens eEPSCs. CTZ-insensitive synaptic depression of the AMPA components was greater in bushy and octopus than in T stellate cells.

Glutamate‐mediated astrocyte‐to‐neuron signalling in the rat dorsal horn

By releasing neuroactive agents, including proinflammatory cytokines, prostaglandins and neurotrophins, microglia and astrocytes are proposed to be involved in nociceptive transmission, especially in conditions of persistent, pathological pain. The specific action on dorsal horn neurons of agents released from astrocytes, such as glutamate, has been, however, poorly investigated. By using patch-clamp and confocal microscope calcium imaging techniques in rat spinal cord slices, we monitored the activity of dorsal horn lamina II neurons following astrocyte activation. Results obtained revealed that stimuli that triggered Ca(2+) elevations in astrocytes, such as the purinergic receptor agonist BzATP and low extracellular Ca(2+), induce in lamina II neurons slow inward currents (SICs). Similarly to SICs triggered by astrocytic glutamate in neurons from other central nervous system regions, these currents (i) are insensitive to tetrodotoxin (TTX), (ii) are blocked by the NMDA receptor (NMDAR) antagonist d-AP5, (iii) lack an AMPA component, and (iv) have slow rise and decay times. Ca(2+) imaging also revealed that astrocytic glutamate evokes NMDAR-mediated episodes of synchronous activity in groups of substantia gelatinosa neurons. Importantly, in a model of peripheral inflammation, the development of thermal hyperalgesia and mechanical allodynia was accompanied by a significant increase of spontaneous SICs in dorsal horn neurons. The NMDAR-mediated astrocyte-to-neuron signalling thus represents a novel pathway that may contribute to the control of central sensitization in pathological pain.

Wnt-5aoccludes Aβ oligomer-induced depression of glutamatergic transmission in hippocampal neurons

BackgroundSoluble amyloid-β (Aβ;) oligomers have been recognized to be early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Wnt signaling plays an important role in neural development, including synaptic differentiation.ResultsWe report here that the Wnt signaling activation prevents the synaptic damage triggered by Aβ oligomers. Electrophysiological analysis of Schaffer collaterals-CA1 glutamatergic synaptic transmission in hippocampal slices indicates that Wnt-5a increases the amplitude of field excitatory postsynaptic potentials (fEPSP) and both AMPA and NMDA components of the excitatory postsynaptic currents (EPSCs), without modifying the paired pulse facilitation (PPF). Conversely, in the presence of Aβ oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well. Co-perfusion of hippocampal slices with Wnt-5a and Aβ oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Aβ oligomers in neuronal cultures. Taken together these results indicate that Wnt-5a and Aβ oligomers inversely modulate postsynaptic components.ConclusionThese results indicate that post-synaptic damage induced by Aβ oligomers in hippocampal neurons is prevented by non-canonical Wnt pathway activation.

A Critical Window for Experience-Dependent Plasticity at Whisker Sensory Relay Synapse in the Thalamus

This study investigated the role of sensory experience in the refinement of whisker sensory relay synapses in the ventral posterior medial nucleus (VPm) of the murine thalamus. Sensory deprivation was done by whisker plucking, and synaptic connectivity was determined by whole-cell patch-clamp recording in acute slices. Sensory deprivation started at P12-P13, but not at P16, disrupted the elimination of VPm relay synapses. The majority of deprived neurons received multiple relay inputs, whereas the majority of nondeprived neurons received a single relay input. Sensory deprivation started a few days earlier at P10, however, had no effect on synapse elimination. The disruption of synapse elimination was associated with a delay in synapse maturation. The AMPA/NMDA ratio of EPSC was significantly smaller in deprived neurons. On the other hand, deprivation had no effect on the peak amplitude or decay time constant of the NMDA component, or the I-V relationship of the AMPA component, nor does it affect the paired-pulse ratio of EPSCs. The reduction in the AMPA/NMDA ratio was already evident within 24 h of whisker plucking, and the effect is associated with a reduction in the amplitude of quantal AMPA events. Thus, P12-P13 is a critical period for experience-dependent refinement at the whisker sensory relay synapse in the VPm.

Relative Roles of Different Mechanisms of Depression at the Mouse Endbulb of Held

Several mechanisms can underlie short-term synaptic depression, including vesicle depletion, receptor desensitization, and changes in presynaptic release probability. To determine which mechanisms affect depression under physiological conditions, we studied the synapse formed by auditory nerve fibers onto bushy cells in the anteroventral cochlear nucleus (the "endbulb of Held") using voltage-clamp recordings of brain slices from P15-P21 mice near physiological temperatures. Depression of both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) excitatory postsynaptic currents (EPSCs) showed two phases of recovery. The fast component of depression for the AMPA EPSC was eliminated by cyclothiazide and aniracetam, suggesting it results from desensitization. The fast component of depression for the NMDA EPSC was reduced by the low-affinity antagonist l-AP5, suggesting it results from saturation. The remaining depression in AMPA and NMDA components is identical and therefore presynaptic in origin. It is likely to result from presynaptic vesicle depletion. Recovery from depression after trains of activity was slowed by the application of EGTA-AM, suggesting that the endbulb has a residual-calcium-dependent form of recovery. We developed a model that incorporates depletion, desensitization, and calcium-dependent recovery. This model replicated experimental findings over a range of experimental conditions. The model further indicated that desensitization plays only a minor role during prolonged activity, in large part because presynaptic release is so depleted. Thus depletion appears to be the dominant mechanism of depression at the endbulb during normal activity. Furthermore, calcium-dependent recovery at the endbulb is critical to prevent complete rundown during high activity and to preserve the reliability of information transmission.

Adenosine A2A Receptors Are Essential for Long-Term Potentiation of NMDA-EPSCs at Hippocampal Mossy Fiber Synapses

The physiological conditions under which adenosine A2A receptors modulate synaptic transmission are presently unclear. We show that A2A receptors are localized postsynaptically at synapses between mossy fibers and CA3 pyramidal cells and are essential for a form of long-term potentiation (LTP) of NMDA-EPSCs induced by short bursts of mossy fiber stimulation. This LTP spares AMPA-EPSCs and is likely induced and expressed postsynaptically. It depends on a postsynaptic Ca2+ rise, on G protein activation, and on Src kinase. In addition to A2A receptors, LTP of NMDA-EPSCs requires the activation of NMDA and mGluR5 receptors as potential sources of Ca2+ increase. LTP of NMDA-EPSCs displays a lower threshold for induction as compared with the conventional presynaptic mossy fiber LTP; however, the two forms of LTP can combine with stronger induction protocols. Thus, postsynaptic A2A receptors may potentially affect information processing in CA3 neuronal networks and memory performance.

Realistic synaptic inputs applied to coupled oscillator model of the dopamine neuron

Midbrain dopamine neurons are involved in motivation and the control of movement, and have been implicated in various pathologies such as Parkinson's disease, schizophrenia and drug abuse. Dopamine neurons in the presence of their afferent inputs in vivo can exhibit one of several firing modes: silence, regular single-spike firing, irregular single-spike firing, and bursting. Bursts in dopamine neurons are thought to convey the reward prediction and salience signals. Dopamine neurons in a slice preparation fire spontaneously in a regular, pacemaker-like manner at a low frequency (~2–3 Hz). This regular firing appears to be driven by a subthreshold oscillation caused by interaction of a low voltage threshold, noninactivating Ca2+ current and a Ca2+-activated small conductance K+ current. Somatic injection of depolarizing bias current can increase the frequency of sustained firing only up to 10 Hz before the neurons go into depolarization block. Bursts observed in vivo have higher instantaneous frequencies. Two theories have been advanced for how higher frequencies are achieved in vivo. One is that during pacemaking, the natural frequencies of the soma and proximal dendrites drive the subthreshold oscillation, whereas during bursting the NMDA input to the dendrites amplifies the current associated with the distal dendritic oscillation, and drives the soma, resulting in high-frequency spiking. The other hypothesis is that the rapidly varying synaptic input (particularly the AMPA component) is not equivalent to a constant depolarizing pulse but this rapid variation can drive faster spiking that can be observed in response to a constant pulse. We have constructed a realistic multicompartmental model to test the contribution of intrinsic and synaptic currents in the dendrites to the firing pattern. The oscillatory dendrites regularize the firing pattern, decrease the frequency compared to a model in which the subthreshold oscillation is confined to the soma, and contribute to grouping of spikes into bursts.